Methods and compositions of reserpine alkaloids with antidepressants for treating hypertension



United States Patent METHODS AND COMPOSITIONS OF RESERPINE ALKALOIDS WITH ANTIDEPRESSANTS FOR TREATING HYPERTENSION John H. Biel, Milwaukee, Wis. (522 Green Bay Road, Lake Bluff, Ill. 60044) No Drawing. Filed June 28, 1965, Ser. No. 467,773 Int. Cl. A61k 27/00 US. Cl. 424-444 9 Claims ABSTRACT OF THE DISCLOSURE Disclosed are pharmaceutical compositions comprising in combination a reserpine alkaloid of the group consisting of alseroxylon, deserpidine, rescinnamine, reserpine and syrosingopine with an anticholinergic-inducing antidepressant of the group consisting of imipramine, desmethylimipramine, amitriptyline, nortriptyline and protriptyline. A diuretic can be included in the compositions. The compositions are useful for treating hypertension. The reserpine alkaloid lowers the blood pressure. The antidepressant agent counteracts depression induced by the reserpine alkaloid and enhances its blood pressure lowering effect.

This invention relates to the treatment of hypertension or high blood pressure. More particularly, this invention is concerned with a new treatment of hypertension and novel compositions used in such treatment.

Reserpine and related Rauwolfia alkaloids including derivatives thereof have been used to lower human blood pressure. Drugs of this type, however, have a number of undesirable and sometimes dangerous side effects. Thus, reserpine produces a central depression in humans which results in sedation and often mental depression leading to suicidal attacks. Furthermore, prolonged consumption of reserpine, particularly at high dose levels, produces undesirable gastrointestinal side effects such as hypersecertion of gastric juice, intestinal pain and spasms which can eventually culminate in a perforated ulcer. These effects are induced, to an appreciable extent, by stimulation of the cholinergic or peripheral sympathetic nervous system of reserpine and related compounds.

Reserpine and compounds related to it inbasic structure or activity induce release or norepinephrine in hu mans from storage sites of the sympathetic nerve endings into the human circulatory system where the released norepinephrine is subjected to metabolic action and converted in part to inactive metabolites such as vanilmandelic acid. Within the storage sites norepinephrine is protected from metabolic attack. The release or norepine phrine from storage sites results in norepinephrine depletion at sympathetic nerve endings and hence a block in sympathetic nerve transmission. Considerable released norepinephrine is not metabolized, however, and is carried back to the sympathetic nerve endings for redeposition there.

According to the present invention, the treatment of hypertension in humans can be effected by the simultaneous, or concomitant, administration of reserpine as a first drug, including related reserpine-like compounds, and a second drug which inhibits return of reserpine-released norepinephrine to storage sites in the peripheral sympathetic nerve endings to suppress accumulation of sufiicient norepinephrine needed to transmit a sympathetic nerve impulse to the effector organ (blood vessel). Normally, a certain quantum of norepinephrine is required to trigger an effective sympathetic stimulus. Since all sympathetic stimuli are transmitted chemically by the hormone norepinephrine a deficiency of the neutrotrans- "ice mitter will result in decreased bombarding of the sympathetic nerve fibres implicated in maintaining high blood pressure.

The method of treating hypertension according to this invention is thus concerned with inducing in a human suffering from hypertension, a multiple chemical interference with sympathetic nerve transmission to create a deficiency of norepinephrine at selective nerve sites responsible for maintenance of vascular tone.

Some of the reserpine alkaloids which can be used in this invention are:

Alseroxylon (Rau-Wolfia extract) Deserpidine 1 l-desmethoxyreserpine) Rauwolfia serpentina Rescinnamine (3,4,5-trimethoxycinnamic ester of methyl reserpate) Reserpine Syrosingopine (carbethoxysyringoyl methyl reserpate) In this specification and claims such compounds and extracts, as well as others having essentially similar activity and having the reserpine nucleus or most of it, are intended to be included within the terms reserpine-like, reserpine-type and reserpine alkaloid.

The second drug needed in practicing this invention is one which inhibits redeposition of norepinephrine at the nerve storage sites. It has been found that such redeposi tion is inhibited by the use of an antidepressive agent which is also an anticholinergic agent such as those of the imipramine and triptyline types including imipramine (I), desmethylimipramine (II), amitriptyline (III), nortriptyline (IV), and protriptyline (V), having the formulae:

Q11) (l I n u YHCiI-LN HC2H4N( CH3)2 (III) i K/Y C H C 2H4N (b) An inhibition of the released norepinephrine to return to the storage sites to which part of it would otherwise normally return and be protected from further metabolic attack.

The two drugs complement each other in bringing about a profound lowering or depletion of norepinephrine in the storage sites making possible an equivalent decrease in blood pressure by administration of lower dosages of reserpine. The lower dosages of reserpine result in a marked decrease in the incidence of side effects.

In addition, the second drug exerts a pronounced antidepressant effect on the central nervous system and thus counteracts and neutralizes any mental depression from chronic administration of reserpine. Furthermore, the second drug elicits a pronounced anticholinergic effect which offsets gastrointestinal side effects produced by reserpine, a cholinergic stimulant.

The combination of a reserpine-like drug with an anticholinergic inducing antidepressant agent, which is advisably not a monoamine oxidase inhibitor, as represented by Formulae I to V, results in both increased therapeutic efficacy in the treatment of hypertension and a substantial lowering of reserpine-induced side effects, thereby increasing substantially the margin of safety for this type of antihypertensive therapy.

By concomitant, and advisably simultaneous, administration to a human of a reserpine-type hypotensive agent and an antidepressant drug of the type represented by Formulae I to V, there is achieved a greater and unexpected hypotensive action than could be achieved by administering reserpine alone. As a result, the two drugs in combination can be administered at dosages substantially below those which cause disturbing side effects and yet optimum hypotensive action is obtained without mental depressant and gastrointestinal side effects. Also, many hypertensive patients, because of their affliction, suffer from a mental depression which the antidepressant drug reduces, thus greatly improving their mental outlook on life and contributing to the over-all therapeutic effect.

To further enhance the antihypertensive effect of the two drugs, a thiazide-type diuretic such as chlorothiazide, trichloromethiazide, dihydrochlorothiazide, dihydrofiumethiazide, chlorthalidone, benzydroflumethiazide and methylchlorothiazide can also be added because it is compatible with the clinical activity of the other two drugs. Chlorthalidone, while it contains a nucleus somewhat different than that of the thiazides just described, is a sulfonamide-containing diuretic and for the purpose of this invention is to be considered within the terminology used when thiazide diuretics are mentioned. Such compounds, and others of the thiazide type, are orally effective and increase diuretic activity in humans at daily dosage amounts of from 1 to 500 mg.

Although the reserpine-like drug and the anti-depressant drug can be administered separately, either simultaneously or concomitantly with each other, with or without the thiazide-type diuretic, it is much more suitable to administer the drugs in unit dosage pharmaceutical compositions which contain an amount of each drug at least adequate when administered one or more dosages at a time to ob tain an effective action in a human. There are, therefore, provided by this invention novel unit dosage pharmaceutical compositions which contain an effective amount of the reserpine-like drug, usually from about 0.1 to 5 mg. of such drug, and an effective amount of an antidepressant drug, usually from about 2 to 100 mg. of such drug, which can be admixed, if advisable, with a pharmaceutical carrier to facilitate forming tablets, capsules, lozenges and liquid formulations. The compositions should generally contain about 0.1 to by weight of active drugs.

Pharmaceutical carriers which are liquid or solid may be used. The preferred liquid carrier is water. Flavoring materials may be included in the solutions as desired.

Solid pharmaceutical carriers such as starch, sugar, talc and the like may be used to form powders. The powders may be used as such for direct administration to a patient or, instead, the powders may be added to suitable foods and liquids, including water, to facilitate administration.

The powders may also be used to make tablets, or to fill gelatin capsules. Suitable lubricants like magnesium stearate, binders such as gelatin, and disintegrating agents like sodium carbonate in combination with citric acid may be used to form the tablets.

A typical tablet can have the composition:

Mg. (1) Reserpine l (2) Imipramine 5 (3) Starch, U.S.P. 57 (4) Lactose, U.S.P. 73 (5) Talc, U.S.P 9 (6) Stearic acid 6 Powders l, 2, 3 and 4 are slugged, then granulated, mixed with 5 and 6, and tableted.

A gelatin capsule can contain the following active drugs:

Mg. Reserpine 0.25 Desipramine 25.0 Trichloromethiazide 4.0

The amount of the reserpine-type antihypertensive, the antidepressant and the thiazide-type diuretic used in the combination will be governed by the activity of the particularly drug used since the activity varies from one member of the drug type to another. The following are typical ranges of dosages which can be used in the combinations:

Alseroxylon 0.5-4

Imipramine 5-50 Deserpidine 0.1-1

Desipramine 5-50 Rescinnamine 0. l-1

A-mitriptyline 5-50 Reserpine 0.1-l

Imipramine 5-10 Reserpine 0.1-1

Desipramine 510 Reserpine 0.1-l

Amitriptyline 5-50 Reserpine 0.1-1

Nortriptyline 550 Reserpine 0.1-1

Protriptyline 5-50 Reserpine 0.1-1

Imipramine 5-50 Chlorothiazide 50-500 Reserpine 0.1-1

Desipramine 5-50 Dihydrochlorothiazide 10-100 Mg. Reserpine 0.1-1 Amitriptyline 5-50 Dihydroflumethiazide 10-20() Reserpine 0.1-1 Nortriptyline 5-50 Chlorthalidone 10-300 Reserpine 0.1-1 Desipramine 5-50 Trichloromethiazide 1-10 Rauwolfiw serptina 0.5-5 Desipramine 5-50 Syrosingopine 0.1-1 Imipramine -10 Such combinations can be formulated into unit dosage forms with or without carriers.

Although the drugs might be administered by other routes, the oral route is most suitable. The number of unit dosages administered daily is to be prescribed by a physician in light of the patients general condition and the results to be sought.

The drug employed in this invention which can be used as the free base are in the form of salts or derivatives so long as the desired biological activity is preserved and adverse effects do not result.

Although the subject invention has primary value in humans, it can also be used in lower animals such as dogs and horses and captive wild animals such as in zoos, and particularly in large mammals.

What is claimed is:

1. The method of lowering blood pressure in a hypertensive human patient, which comprises orally administering to said human a unit dosage pharmaceutical composition containing about 0.1 to 5 mg. of a reserpine alkaloid selected from the group consisting of alseroxylon, deserpidine, rescinnamine, reserpine and syrosingopine and about 2 to 100 mg. of an antidepressant selected from the group consisting of imipramine, desmethylimipramine, amitriptyline, nortriptyline and protriptyline, said composition containing the reserpine alkaloid in an amount effective to lower blood pressure and containing said antidepressant in an amount suflicient to suppress the mental depressant and gastrointestinal side effects induced by the reserpine alkaloid.

2. The method of claim 1 in which the pharmaceutical composition additionally contains about 1 to 500 mg. of a diuretic selected from the group consisting of chlorothiazide, trichloromethiazide, dihydrochlorothiazide, dihydrofiumethiazide, chlorthalidone, benzydrofiumethiazide and methylchlorothiazide, in an amount sufiicient to induce a diuretic effect in the patient.

3. The method of lowering blood pressure in a hypertensive human patient, which comprises orally administering to said human a unit dosage pharmaceutical composition containing a member selected from the group consisting of 0.5 to 4 mg. of alseroXylon, 0.1 to 1 mg. of deserpidine, 0.1 to 1 mg. of rescinnamine, 0.1 to 1 mg. of reserpine and 0.1 to 1 mg. of syrosingopine, in combination with a member selected from the group consisting of 5 to 50 mg. of imipramine, 5 to 50 mg. of desipramine, 5 to 50 mg. of amitriptyline, 5 to 50 mg. of nortriptyline and 5 to 50 mg. of protriptyline.

4. The method of lowering blood pressure in a hypertensive human patient which comprises orally administering to said human a unit dosage pharmaceutical composition containing one of the combinations A to M:

Alseroxylon 0.5-4

Imipramine 5-50 Deserpidine 0.1-1

Desipramine 5-50 Rescinnamine 0.1-1

Amitriptyline 5-50 Reserpine 0.1-1

Imipramine 5-10 Reserpine 0.1-1

Desipramine 5-10 Reserpine 0.1-1

Amitriptyline 5-50 Reserpine 0.1-1

Nortriptyline 5-50 Reserpine 0.1-l

Protriptyline 5-50 Reserpine 0.1-1

Imipramine 5-50 Reserpine 0.1-1

Desipramine 5-50 Dihydroflumethiazide 10-100 K Reserpine 0.1-l

Amitriptyline 5-50 Dihydroflumethiazide 10-200 Reserpine 0.1-1

Nortriptyline 5-50 Chlorthalidone 10-300 Reserpine 0.1-1

Desipramine 5-50 Trichloromethiazide 1-10 5. A pharmaceutical composition for lowering blood pressure in unit-dosage form containing a member selected from the group consisting of 0.5 to 4 mg. of alseroxylon, 0.1 to 1 mg. of deserpidine, 0.1 to 1 mg. of rescinnamine, 0.1 to 1 mg. of reserpine and 0.1 to 1 mg. of syrosingopine, in combination with a member selected from the group consisting of 5 to 50 mg. of imipr'amine, 5 to 50 mg. of desipramine, 5 to 50 mg. of amitriptyline, 5 to 50 mg. of nortriptyline and 5 to 50 mg. of protriptyline.

6. A pharmaceutical composition for lowering blood pressure according to claim 5 additionally containing a member selected from the group consisting of 50 to 500 mg. of chlorothiazide, 10 to mg. of dihydrochlorothiazide, 10 to 200 mg. of dihydroflumethiazide, 10 to 300 mg. of chlorthalidone and l to 10 mg. of trichloromethiazide.

7. A pharmaceutical composition for lowering blood pressure containing 0.1 to 1 mg. of reserpine and 5 to 50 mg. of desipramine.

7 8. A pharmaceutical composition for lowering blood pressure containing 0.1 to 1 mg. of reserpine and 5 to 50 mg. of imipramine.

9. A pharmaceutical composition for lowering blood pressure containing 0.1 to 1 mg. of reserpine and 5 to 50 mg. of amitriptyline.

References Cited UNITED STATES PATENTS 3,320,129 5/1967 Gansser et al. 424244 OTHER REFERENCES Aceto et al.: Toxicology and Applied Pharmacology, 7, 329-336, 1965, citing Suker et 211., Fed. Proc. 20, 231,

1961 and Ann. New York Acad. Sci, 96, 279, 1962 and Wilson et a1. P.S.E.B.M., 109, 847, 1962.

Modern Drug Encyclopedia, 8th Ed, 1961, pp. 1131, 1132,1133, 1291.

Benson et al.: Tranquilizing and Antidepressive Drugs, (Thomas Publ.) Aug. 29, 1962, pp. 55, 80, 81.

Vernier et 211.: First Hahnemann Symposium on Phychosomatic Med., 1962, pp. 683-690.

10 STANLEY J. FRIEDMAN, Primary Examiner US. Cl. X.R.

3 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 517 a ed June 23, 1970 Inventor(s) John H B161 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1 line 45 change "of" to by Column 1 line 47 change "or" to of Column 1, line 53 change "or" to of Column 7, line 9 insert Wilson and Jones American Drug Index for 1963, pp. 630-632, 663, 386 and 744 sumo AND mum one-1gp Attest:

Edward M. Fletcher, Ir. Wm]: M E m Attesnng Officer Commissioner of Patantfl 

